Template:ABSTRACT PUBMED 20958055

{{Abstract
 * ABSTRACT=Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure-activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((+/-)-32 and (+/-)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-&#91;2-(3-fluorophenethylamino)ethoxy&#93;pyrrolidin-4'-yl}methyl}-4-methy lpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-&#91;2-(3-fluorophenethylamino)ethylamino&#93;pyrrolidin-4'-yl}m ethyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) ( J. Am. Chem. Soc. 2010, 132 ( 15 ), 5437 - 5442 ). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.
 * REFERENCE=Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives., Ji H, Delker SL, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB, J Med Chem. 2010 Oct 19. PMID:20958055

}}